Abstract: The generalized HIV epidemics in sub-Saharan Africa are characterized by high population prevalence, low knowledge of HIV serostatus, and the majority of HIV transmissions occurring within stable heterosexual partnerships. No single HIV prevention strategy will control the African HIV epidemic;thus, multi-layered and multi-component prevention will be needed. We propose to develop a coordinated, multi-component HIV prevention package of evidence-based biomedical and behavioral interventions that will be individually-tailored and targeted to maximize coverage and impact on HIV incidence in an African population. The package will be delivered through a community-based platform of household-based VCT (HBCT) to enhance population-level coverage and knowledge of serostatus, coupled to community-level delivery of key prevention messages. HBCT has been demonstrated to be feasible, acceptable and cost-effective in East Africa and provides a uniquely suitable mechanism to identify persons unaware of their HIV infection, HIV discordant couples, and high-risk HIV uninfected persons - high priority populations for targeting HIV prevention. We hypothesize that, using a HBCT platform, it is feasible and acceptable to deliver an individualized "HIV prevention prescription" to critical subpopulations with high levels of coverage, combining appropriate biomedical and behavioral interventions that are likely to synergistically reduce population-level HIV transmission in the generalized African heterosexual epidemic. Our Specific Aims are to: 1. Conduct epidemiologic analyses, systematic reviews, and mathematical modeling to identify modifiable determinants of heterosexual HIV transmission with the highest population-attributable fraction in sub-Saharan Africa, estimate the impact of targeted prevention strategies directed at these determinants, and select components of a prevention package based on these analyses. 2. Pilot data collection for identification of highest-risk individuals (HIV discordant couples, HIV-infected persons, and HIV-negative persons with high-risk behaviors) with integration and targeting of behavioral and biomedical prevention interventions into population-based HBCT programs. 3. Design a community-randomized effectiveness trial of a comprehensive, targeted, biomedical and behavioral HIV prevention package for East and southern Africa in the context of HBCT. Our multi-disciplinary team includes epidemiologists, mathematical modelers, biostatisticians, and investigators with extensive expertise in conducting multi-center biomedical and behavioral intervention trials in Africa. We propose HBCT as a platform to deliver community-wide behavioral assessment of HIV risk and to provide individualized, multi-component biomedical (e.g., male circumcision, ART) and behavioral HIV prevention packages to at-risk individuals. This targeted "prevention prescription" will be the foundation for the product of this application: a design and protocol for a future community-randomized trial of a multi-component HIV prevention package for the generalized heterosexual epidemics in sub-Saharan Africa. Based on epidemiologic analyses and mathematical modeling of HIV transmission determinants in generalized heterosexual epidemics in Africa and potential interventions, we will design an evidence-based HIV prevention package and a community-randomized trial of this prevention package which will be implemented on a platform of home-based voluntary HIV counseling and testing to target high-risk persons and achieve high levels of coverage.